Integrative Interventions

Conventional approaches are highly effective in the treatment of skin cancer, and the earlier the cancer is detected, the better the likelihood of a successful outcome. While the integrative interventions listed below may complement conventional skin cancer treatment, anyone who identifies a suspicious lesion on their skin should seek medical evaluation from a dermatologist right away.

B-Vitamins

In mice, niacin (vitamin B3) lowered incidence of UVB-induced skin tumor formation in a dose-dependent manner (from 68% in control animals to 28% in animals supplemented with niacin at 1% of their diet) and reduced UVB-induced immune suppression (Gensler 1999). Oral nicotinamide (500-1500 mg/day) given to 61 human volunteers significantly reduced immunosuppression from simulated solar UV irradiation compared to placebo (Yiasemides 2009). In a comprehensive review of 15 studies of folate consumption and cancer risk, higher folate consumption was linked to an overall risk reduction in the incidence of melanoma (53% over 3 trials with a total of 19 128 participants) (Qin 2013).

Probiotics

In addition to their potential functions in gastrointestinal health, animal models suggest certain strains of probiotic bacteria may minimize UV-induced skin photodamage, potentially by modulating inflammatory response. Administration of the Bifidobacterium breve strain Yakult (BBY) to hairless mice for 9 and 14 days reduced skin elastase activity (a marker for photodamage) and inflammatory cytokine interleukin-1 beta (IL-1β) production arising from 4 consecutive days of UV-irradiation exposure (Sugimoto 2012). Lipoteichoic acid, a component of the cell wall of the probiotic strain Lactobacillus rhamnosus GG, had immunostimulatory effects and was photoprotective in hairless mice exposed to UV radiation and delayed the appearance of skin tumors (Weill 2012). A similar protection from UV immune suppression was observed in hairless mice after 10 days of supplementation with Lactobacillus johnsonii La1 (Guéniche 2006).

Tea Polyphenols

The anti-inflammatory effects of green tea polyphenols have been substantiated by dozens of laboratory and animal studies (Singh 2010). The polyphenol epigallocatechin gallate (EGCG) exerts its anti-inflammatory effects by inhibition of the NF-κβ signaling pathway, which results in decreased expression of several inflammatory mediators (such as IL-1β) in cell culture experiments (de Mejia 2009). Laboratory experiments have shown that EGCG suppresses melanoma proliferation through the inhibition of NF-κβ, which in turn led to decreased cell growth (Ellis 2011). Several studies of topical and oral green tea in mice have demonstrated the inhibition or delay of UVB-induced skin tumor development by reducing inflammation, inhibiting angiogenesis (recruitment of blood vessels by the tumor), reducing DNA damage, promoting rapid DNA repair, and reducing tissue adiposity (Katiyar 2007; Katiyar 2011; Payette 2010; Yang 2011). In a study conducted on human skin samples, topical green or white tea conferred protection against UV-induced detriments to cutaneous immunity (Camouse 2009).

Polypodium

Polypodium leucotomos, a species of tropical fern with anti-inflammatory and antioxidant properties, has long been used by Native Americans as a treatment for inflammatory disorders (Jansen 2013; Aguilera 2013). Polypodium extracts have been studied as an adjunctive therapy for several skin conditions, atopic dermatitis (Ramirez Boscá 2012), and photodermatoses (sunlight-induced skin rashes) (Caccialanza 2011). In mice fed Polypodium extract (300 mg/kg) for 10 days prior to exposure to UV irradiation, Polypodium pre-treatment lowered the activity of COX-2 (an inflammatory enzyme implicated in cancer progression) compared with control animals. Evidence of DNA damage was also reduced in the extract-fed mice (Zattra 2009). In 61 patients with melanoma, pre-treatment with Polypodium extract (1080 mg) before exposure to UV-radiation increased the minimal erythematous dose (the amount of UV radiation to which skin can be exposed before sunburn) compared to baseline (Aguilera 2013). This reduction in UV sensitivity was seen in 65% of the patients in the study.

Red Orange Complex

Red oranges, also known as blood oranges, have rinds resembling traditional oranges, but contain deeply-pigmented flesh rich in bioactive compounds. Three red orange varieties from the Mediterranean region – Citrus sinensis var. Moro, Tarocco, and Sanguinello – have gained scientific interest as an abundant source of powerful phytoceuticals including anthocyanins, flavones, hydroxycinnamic acids, and ascorbic acid (Bonina 2002; Saija 1998). These red orange constituents have been shown to exert potent antioxidant action and bolster intrinsic free radical defenses within the body when administered as a supplement at 50 mg per day to diabetics (Bonina 2002). Red orange constituents also appear to benefit cardiovascular health; in a study on 19 subjects between ages 27 and 56 with increased cardiovascular risk, supplementation with 500 mL of red orange juice daily for 7 days significantly improved a measure of endothelial function and reduced markers of systemic inflammation in blood samples compared to placebo (Buscemi 2012). Evidence for photoprotective properties of red orange extract make it appealing as a skin-protection agent. One study showed that topical application of red orange extract reduced UVB-induced erythema in healthy volunteers (Saija 1998). In a study on 18 volunteers aged 26-47, subjects took 100 mg of red orange complex twice daily for 15 days, then researchers tested the sensitivity of participants’ skin to UVB radiation. Supplementation with red orange complex led to a roughly 35% reduction in the intensity of skin erythema following UVB exposure, suggesting consumption of 200 mg daily of red orange complex may mitigate the likelihood of developing sunburn (Bonina 2008).

Grape Seed Extract

Grape seed extract contains proanthocyanidins, phytochemicals that exhibit antioxidant and anti-inflammatory properties (Jensen 2010). In mouse models and cell culture experiments of UV-induced skin damage, grape seed proanthocyanidins have enhanced DNA repair (Vaid, Sharma 2010), reduced immune suppression (Vaid 2011) and oxidative stress (Sharma 2007), and prevented tumor growth (Jensen 2010). In a case-control observational study, supplement usage was compared between 415 patients diagnosed with squamous cell carcinoma and 415 age-, sex-, and race-matched control subjects with no history of skin cancer. The comparison revealed that participants who consumed grape seed extract had a 74% decreased risk of cutaneous squamous cell carcinoma compared to those that did not (Asgari 2011). The same study demonstrated a borderline significant risk reduction among multivitamin users. No information on dose or duration of supplement use was obtained in this study. When applied topically to 10 healthy volunteers, grape seed extract decreased the incidence of sunburned keratinocytes and cells with UV-induced mutations in the DNA-protective protein p53 after experimental exposure to two doses of UV irradiation (Yuan 2012).

Fish Oil

Fish oil is a source of omega-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]), which cannot be efficiently synthesized by humans but are nonetheless essential for several metabolic processes. Omega-3 fatty acids may help reduce UV-induced immune suppression (an important component of skin carcinogenesis). In a study of 79 women with cutaneous nickel allergies, participants took 5 g/day of supplemental omega-3 (70% EPA plus 10% DHA) for 3 months. After supplementation, skin was exposed to 3 daily immunosuppressing doses of solar UV irradiation and then exposed to nickel sulfate ointment. UV-induced immune suppression appeared to be mitigated in the participants taking omega-3 supplements compared to the control group, although the results were not statistically significant (Pilkington 2013).

Melatonin

Melatonin is the main secretory product of the pineal gland in the brain and regulator of circadian rhythm; its recognized anti-oxidation and membrane stabilization actions may make it a promising candidate as a sun-protective agent. In a systematic review of 4 randomized controlled human trials (58 total participants), topical melatonin (0.5-2.5%) demonstrated an overall significant suppression of UV-induced erythema (sunburn) when applied prior to UV exposure (Scheuer 2013). Melatonin has also demonstrated reductions of chemical-induced skin carcinogenesis in a mouse model (Man'cheva 2011). Evidence suggests that higher urinary levels of a major melatonin metabolite may be associated with reduced skin cancer risk. In a study on 140 subjects – 70 with skin cancer and 70 healthy controls – healthy individuals without skin cancer had significantly higher urinary levels of 6-sulfatoxymelatonin over a 24-hour period compared to skin cancer patients. The researchers who conducted the study concluded “It seems that a low level of 24-hour urinary 6-sulfatoxymelatonin renders human beings prone to skin cancer” (Ghaderi 2014).

Vitamin D

Vitamin D is important in the growth regulation of keratinocytes (Rosen 2012). It suppresses proliferation of cancer cells in tumor tissue, suggesting that vitamin D and its metabolites may be protective against cancer (Gandini 2009). Several studies have examined the link between vitamin D status and melanoma. Some studies found mixed results, while others revealed that higher dietary vitamin D intake is associated with a decrease in the risk for melanoma. Lower serum vitamin D levels were sometimes found in patients with more advanced stage melanoma, and a survival advantage was demonstrated in those with higher serum vitamin D levels (Berwick 2013). While the illustration of a direct preventative effect of vitamin D on skin cancer awaits further study, supplemental vitamin D may be beneficial in maintaining adequate vitamin D levels without sun exposure. Approximately 90% of vitamin D is produced in the skin by exposure to sunlight (specifically UVB radiation, the same radiation that increases cancer risk) (Stroud 2008), and supplemental vitamin D may be a better option for maintaining vitamin D levels, especially in individuals at elevated risk for skin cancer (Barysch 2010).

Resveratrol and Pterostilbene

Much of the recent research on the phytochemical resveratrol has focused on its potential in cancer chemoprevention and treatment, inflammation, and oxidative stress. In cell culture, it has been shown to induce death in human epidermoid carcinoma and melanoma cells and reduce pro-oxidant production by cancer cells (Ndiaye 2011). It was also shown experimentally to increase the anti-cancer toxicity of the chemotherapy drugs temozolomide (Temodar®), cisplatin (Platinol®), and etoposide (Etopophos®), and the efficacy of radiation therapy against melanoma cell lines, while having no effect on normal human fibroblasts (Osmond 2012; Heiduschka 2014). In mouse models, oral and topical resveratrol significantly reduced UVB-mediated inflammation, free-radical generation, infiltration of white blood cells, tumorigenesis, and malignant conversion of benign skin papillomas to squamous cell carcinomas (Ndiaye 2011). Peritumoral injections of resveratrol in a mouse model of uveal (ocular) melanoma demonstrated its ability to induce cancer cell death and tumor regression (van Ginkel 2008). An analog of resveratrol, pterostilbene, may also inhibit skin carcinogenesis by reducing inflammatory gene expression; in a mouse model, it reduced expression of the pro-inflammatory enzyme COX-2 and the multiplicity of skin tumors (papilloma) induced by chemical carcinogens (Tsai 2012).

Curcumin

Curcumin has been investigated in a variety of human cancers including pancreatic, prostate, breast, and head and neck cancer (Sonavane 2012). In cell culture, curcumin inhibits growth of squamous cell carcinoma and melanoma cells (Sonavane 2012; Caltagirone 2000). In mouse models, topical application of low dose curcumin along with the carcinogen 12-O-tetradecanoylphorbol-13-acetate (TPA) reduced the ability of the carcinogen to induce skin tumor formation and DNA damage (Huang 1997). Both topical and dietary curcumin equally reduced the growth of human squamous cell carcinoma cells implanted in the skin of mice (Sonavane 2012).

Quercetin

Quercetin intake has been associated with decreases in colorectal and lung cancer risk; its potential anti-carcinogenic effects stem from its anti-inflammatory and antioxidant activity (Jung 2013). In cell culture experiments, quercetin was toxic against melanoma cancer cells (Sak 2014; Caltagirone 2000) and reduced the incidence of skin carcinogenesis caused by the carcinogens 12-O-tetradecanoylphorbol-13-acetate (TPA) and 7,12-dimethylbenz(a)anthracene (DMBA) by 35% when supplied at 0.02% in the diet of mice (Jung 2013). In a mouse model of melanoma metastasis, quercetin reduced the number of melanomas in mouse lungs by up to 71% when fed to mice at a concentration of 50 mg/kg (or about 324 mg for an 80 kg human) (Caltagirone 2000).

Coenzyme Q10

Coenzyme Q10 (CoQ10) is essential for normal cellular respiration and energy production, and its deficiency has been suggested to contribute to abnormal cell division patterns, which may favor cancer cell growth. Levels of CoQ10 are reduced in several cancers, including melanoma, and patients with melanoma who presented with low CoQ10 levels were found to have significantly higher risks of metastatic dissemination in one study (Rusciani 2006). In patients with stage I and II melanoma that had been treated by surgical excision, adjuvant therapy with CoQ10 (200 mg, twice daily) plus IFN-α for 3 years resulted in only about one-tenth the occurrence of tumor metastasis over an 8-year period compared to patients treated with interferon alone (Rusciani 2007).

Carnosol

Carnosol is an antioxidant principle from rosemary (Rosmarinus officinalis), which along with the related compound carnosic acid, is responsible for about 90% of rosemary’s antioxidant activity. In cell culture, it sensitizes melanoma cells to the damaging effects of X-ray radiation, increasing cellular death by 34% compared to radiation alone (Alcaraz 2013). It also inhibited the migration and invasion of melanoma cells in a cell culture assay (Huang 2005).

Mistletoe

Injectable preparations from the European mistletoe (Viscum album L.) are prescribed for cancer patients in several European countries (Horneber 2008). Several small pilot studies investigating mistletoe extract in cancer therapy have shown variable efficacy (Ernst 2003; Horneber 2008). One epidemiological study looked at patients who received surgical treatment for stage II or III melanoma at one of 35 German or Swiss hospitals and medical practices between 1985 and 2001. A group of 329 patients that received fermented mistletoe extract injections as part of their post-operative therapy were compared to 357 patients who did not. Over a 6.8 year period, patients that received mistletoe therapy demonstrated a significant increase in overall survival compared to the control group, although the rate of metastasis was not different between the groups except for lung/mediastinal metastases, which were significantly more rare in the group receiving mistletoe (Augustin 2005).

Honokiol

Honokiol is a derivative of Magnolia officinalis, a traditional Chinese therapy with antiangiogenic, anxiolytic, anti-inflammatory, and antitumor properties (Mannal 2011). In cell culture experiments, Honokiol extracts were shown to be toxic to human melanoma cells, by stopping their proliferation and growth, and increasing the production of apoptotic enzymes and mitochondrial depolarization (signs of apoptosis – programmed cell death) (Mannal 2011; Kaushik 2012). In a mouse model, topical application of high dose (60 mcg) Honokiol to the mice prior to UV exposure reduced tumor incidence by 40% compared to control animals (Guillermo 2012).

Ukrain

Ukrain is a semisynthetic derivative of alkaloids from Chelidonium majus that has been reported to have a selective toxic effect on tumor cells (Skivka 2011). It is licensed for use as a cancer therapy in several former Soviet states. Ukrain is given by intravenous injection and has been studied as a primary or adjuvant therapy for treating several human cancers (colorectal, bladder, pancreatic, and breast) (Ernst 2005). Published case reports suggest its efficacy in maintaining remission in two patients with melanoma (Hamler 1996; Stabuc 1996). In mouse models, Ukrain injections (7 times per day every third day) reduced tumor growth from both low- and high-metastatic melanoma variants (Skivka 2011).

Modified Citrus Pectin

Modified citrus pectin (MCP) is a water-soluble, indigestible polysaccharide isolated from the peel and pulp of citrus fruits, and it is modified using high pH and temperature treatment (Glinsky 2009). MCP, which has been studied as a metal chelating agent, has been reported to reduce heavy metal burden in several human studies (Crinnion 2008). Its potential activity against metastatic cancer is related to its ability to inhibit the function of the pro-carcinogenic factor galectin-3. Galectin-3 is a galactose-binding protein produced in excess in cancer cells, which protects them from self-destruction and facilitates their adhesion to the walls of blood vessels during metastasis (Glinsky 2009). Pectin is rich in galactoside residues and may bind and inhibit the activity of galectin-3; in mouse models, pre-incubation of MCP with B16-F1 melanoma cells reduced their ability to cause lung metastases by 90% when both were injected into test mice (Platt 1992). MCP also reduced the ability of melanoma cells to anchor and grow on a semi-solid growth surface in a cell culture experiment (Inohara 1994).

Fermented Wheat Germ Extract

Fermented wheat germ extract (Avemar®, AvéULTRA®), a patented natural preparation obtained via fermentation of wheat germ with the yeast Saccharomyces cerevisiae, has shown promise as an anticancer agent in several preclinical and clinical studies (Hidvegi 2002; Mueller 2011). It is approved in Europe as a “dietary food for special medical purposes for cancer patients” (Demidov 2008).

Studies indicate fermented wheat germ extract combats cancer via several mechanisms including inhibition of glucose uptake in cancer cells, suppression of metastasis, mitigation of cancer cell proliferation, and modulation of the immune system. It also appears not to reduce efficacy or enhance toxicity of conventional chemotherapy. Fermented wheat germ extract contains a multitude of molecular compounds, but evidence suggests that two glucosides – 2-methoxy benzoquinone and 2,6-dimethoxy benzoquinone – are partially responsible for its biological properties (Mueller 2011).

In a randomized clinical trial of 52 patients with high-risk stage III skin melanoma, adjuvant chemotherapy with dacarbazine was compared to dacarbazine plus fermented wheat germ extract. Following surgery, 26 patients were allocated to receive dacarbazine alone and 26 were allocated to receive dacarbazine plus 8.5 g daily of fermented wheat germ extract. Dacarbazine was given in 5-day infusion cycles once monthly for up to 4 months or until the disease progressed and treatment with fermented wheat germ extract alone continued for up to 12 months. At the 7-year follow-up period, progression-free survival was greater in the fermented wheat germ extract plus dacarbazine group (mean 55.8 months) compared to the dacarbazine-only group (mean 29.9 months). Overall survival was also greater in the subjects that received fermented wheat germ extract (mean 66.2 months) compared to those that received dacarbazine alone (mean 44.7 months). The researchers concluded “The inclusion of Avemar into the adjuvant protocols of high-risk skin melanoma patients is highly recommended” (Demidov 2008).

Active Hexose Correlated Compound

Active hexose correlated compound (AHCC) is derived from several species of Basidiomycete mushrooms. It is comprised of polysaccharides, amino acids, lipids, and minerals. Evidence has revealed AHCC to be a powerful immunomodulator, bolstering resistance to infections. It also possesses anticancer properties. In a preclinical study, AHCC delayed tumor development in mice inoculated with melanoma cells. It also enhanced growth and activity of several antitumor immune cells in this study. These findings led the researchers to conclude “…our results demonstrate that AHCC can enhance tumor immune surveillance through regulating both innate and adaptive immune responses”(Gao 2006).

AHCC may represent a valuable adjuvant therapy for individuals receiving systemic cancer treatment, as it has been shown to reduce the adverse effects of chemotherapy in preclinical and clinical studies (Ito 2014; Shigama 2009; Hangai 2013; Hirose 2007). A safety study found that AHCC is generally well tolerated in healthy volunteers and does not cause laboratory abnormalities (Spierings 2007).​​

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